Cis-regulatory circuitry underlying hedgehog mediated limb development

摘要： Hedgehog(HH)信号通路是器官发育的主要调节因子，它利用初级的 纤毛通过GLI转录因子调节其转录输出。HH信号转导的作用 主要是通过降低GLI靶基因的抑制来介导的，在没有HH抑制的情况下 通过一种未知的机制转录。这项提议试图理解GLI抑制者是如何 调节正常发育中的刺猬信号，以及这种信号在纤毛疾病中是如何改变的。我们假设 GLI抑制物通过调节增强子上的染色质修饰来抑制基因表达。我们会 确定GLI抑制是否通过组蛋白脱乙酰酶复合体的募集而发生。我们还将 确定GLI增强子何时首次获得可及染色质，以及它们是否与启动子相互作用 需要HH信号。我们进一步假设GLI蛋白在HH之前抑制增强子活性 激活。通过测试，我们将提供关于早期HH形态起源的第一个详细信息 反应并确定在人类纤毛疾病的小鼠模型中GLI转录动力学是否发生改变。 总的来说，这些目标将提供对GLI所依据的过程和时间动态的关键见解 蛋白质与染色质相互作用并调节染色质以抑制转录。此外，他们将决定如何 GLI转录网络首先在纤毛疾病中建立和改变，提供了对GLI如何 在这些综合征中，调节失调会导致结构性出生缺陷。

Abstract: The Hedgehog (Hh) signaling pathway is a major regulator of organ development that utilizes the primary cilium to regulate its transcriptional output through the GLI transcription factors. The effects of Hh signaling are primarily mediated through de-repression of GLI target genes, which in the absence of Hh inhibit transcription through an unknown mechanism. This proposal seeks to understand how GLI repressors regulate Hedgehog signaling in normal development and how this is altered in ciliopathies. We hypothesize that GLI repressors inhibit gene expression by regulating chromatin modifications at enhancers. We will determine if GLI repression occurs through the recruitment of a Histone deacetylase complex. We will also establish when GLI enhancers first acquire accessible chromatin and if their interactions with promoters require Hh signaling. We further hypothesize that GLI proteins repress enhancer activity prior to Hh activation. By testing this, we will provide the first detailed information about the early Hh morphogen response and determine if GLI transcriptional dynamics are altered in a mouse model of human ciliopathies. Collectively, these aims will provide key insights into the processes and temporal dynamics by which GLI proteins interact with and regulate chromatin to repress transcription. In addition, they will determine how GLI transcriptional networks are first established and altered in ciliopathies, providing insight into how GLI dysregulation causes structural birth defects in these syndromes.